Effects of antipsychotics on neurogenesis in animals Initial studies detected increased neurogenesis in the gerbil hippocampus following haloperidol

treatment,195 but not in the rat hippocampus.145 Two more recent studies found that haloperidol did not affect neurogenesis,196,197 although a study that used osmotic pumps (instead of daily intraperitoneal injections or delivery in drinking water) found that haloperidol increased neural stem cell (NSC) proliferation Inhibitors,research,lifescience,medical in the adult rat forebrain.198 Furthermore, the researchers demonstrated that this proliferation was mediated through D2 receptor stimulation in vitro, suggesting that under certain conditions, haloperidol could promote neurogenesis through its suppression of D2-mediated pathways that normally prevent NSC proliferation. Atypical antipsychotics have shown a more consistent profile of enhancing neurogenesis, but do not necessarily increase neuronal survival or differentiation

into adult neurons. Chronic treatment of rats with clozapine or olanzapine, for example, augmented the number of BrdU-labeled cells in the dentate gyrus196 or Inhibitors,research,lifescience,medical prefrontal cortex and dorsal striatum.197 Although both studies detected increased proliferation of precursor cells, neither found a significant difference in the number of BrdU-positive, mature neurons in the weeks following treatment with antipsychotics. Quetiapine has also been Inhibitors,research,lifescience,medical shown to reverse the inhibition of hippocampal neurogenesis caused by chronic restraint stress, and significantly increase the number of BrdU-labeled immature neurons detected compared with vehicle-treated, stressed rats.199 Effect of antipsychotics Inhibitors,research,lifescience,medical on NAA levels, brain volume, and density in patients Studies conducted with schizophrenic patients have examined NAA measures Inhibitors,research,lifescience,medical and volumetric brain changes using 1H-MRS and MRI, Proteasome purification respectively, to elucidate the effects of chronic antipsychotic treatment. Patients treated with atypical antipsychotics had higher NAA measures in the frontal lobes200 and anterior cingulate gyrus201 than those treated with typical antipsychotics. Another

study measured NAA changes during ADP ribosylation factor antipsychotic treatment and after cessation for at least 2 weeks in individual patients using a within-subject design and found significant decreases (~9%) in NAA levels in the dorsolateral prefrontal cortex after ending antipsychotic treatment; no differences were found in other brain regions.202 Schizophrenia, the disorder most often treated with antipsychotics, is well-known to be associated with reduced regional volumes, increased ventricle size,203 and deteriorating course,204 making it difficult to distinguish volumetric changes induced by antipsychotic treatment. Overall, studies suggest that there are differences in the brain volumes of patients treated with antipsychotics compared with controls, or within groups of patients treated chronically with typical versus atypical antipsychotics; for a thorough analysis, see ref 186.